Voltage-gated potassium (Kv) channels regulate cell membrane potential and control a variety of cellular processes. Kv1.3, a Shaker-related Kv channel is expressed in several tissues and believed to participate in cell volume regulation, apoptosis, T cell activation, and renal solute homeostasis. Channel activity is regulated, in a complex manner, by threonine and serine phosphorylation. Serotonin and insulin can both down-regulate the activity of the Kv1.3 channel. In the case of insulin, channel inhibition is observed in the olfactory bulb, and is mediated by phosphorylation of multiple threonine sites. To investigate the function of Kv1.3 in vivo, we carried out preliminary studies using Kv1.3 deficient mice (Kv1.3-/-) generated by gene targeting. Examination of these mice revealed that they weigh less and are more sensitive to the glucose-lowering action of insulin than control littermates. Furthermore, the phenotype observed in Kv1.3-/- mice was recapitulated by the pharmacological blockade of Kv1.3 in wild-type (wt) and diabetic mice, suggesting that Kv1.3's action on insulin sensitivity is independent of body weight. Moreover, inhibition of Kv1.3 channel activity in a skeletal muscle cell line (L6) significantly increased cell glucose uptake. Taken together, these data Kv1.3 strongly support the notion that Kv1.3 and its signaling pathway represent a novel component of the homeostatic mechanisms that regulate glucose metabolism. As such, we believe further investigation is warranted, from the standpoint of gaining a more detailed physiological understanding of the process and of uncovering potential targets for the development of drugs useful in the management of diabetes. While the effect of Kv1.3 on the regulation of body weight is of significant physiological and clinical interest, the current proposal is limited to studying its role in glucose homeostasis. The broad aims of the work are to elucidate the cellular and molecular mechanisms by which Kv1.3 modulates peripheral glucose metabolism and cause increased insulin sensitivity. In the context of our preliminary work, we propose to test if Kv1.3 modulate glucose uptake via an insulin-dependent pathway, and to examine the cellular mechanisms that mediate the action of Kv1.3 on glucose metabolism.